Mercaptopropionic acid derivatives



3,246,025 Patented Apr. 12, 1966 n ed States p i g 3,246,025MERCAP'IOPROPKONXC ACID DERIVATIVES Itaru Mita, Ashiya-shi, 'HyogoPrefecture,- Nobuo Toshioka, Hi'gashi Yodogav'va-ku, Osaka, and ShiroYamamoto, Higashi Nada-ku Kobe-shi, Japan, assignors to SantenPharmaceutical Co., Ltd., Osaka, Japan, a corporation of Japan I NoDrawing. Filed Sept. 13, 1962, Ser. No. 223,539 Claims priority,application Japan, Nov. 2, 1961,

sis/39,905 7 Claims. (Cl. 260-455) The present invention relates tonovel derivatives of mercaptopropionic acid and their preparation andmore particularly to -and tl-mercaptopropionylglycine, their amides andesters and intermediates therefor.

The new derivatives are useful as therapeutic agents for the treatmentof drug intoxication and poisoning due to mercury and arsenic compoundsand have wide application'as antidotes and for. strengthening liverfunction while havingvery low toxicity themselves. 3

According to the present invention, the mercapto radical of aorB-mercaptopropionic acid is protected by a substituent which can easilybe removed in a suc ceeding reaction. then halogenated usinga'conventional haolgertating agent to convert the carboxylic radical'toacid halide, condensed with glycine to form the correspondinga'uor 8mercaptopropionylglycine derivative, and the protective substituentremoved by suitable chemiantidotes.

wherein R is a radical readily convertible to hydrogen by suitablereaction and may be, for example,

etc. and X is a halogen atom. ,8- Mercaptopropionylglycine is similarlyprepared as follows:

R having the above meanings.

The com-pounds aand f3- mercaptopropionylglycine exhibit very littletoxicity when compared with sulfur compounds which have been known asantidotes, show remarkable antido'tal effect to such poisons asmercuryand organoarsenic compounds, and, in addition, exhibit recoveringaction for dysfunction of liver and leuk'openia caused by administrationof drugs, as shown by Tables I, ll, and ill. The invention offers noveltherapeutic agents useful for strengtheing function of liver and asTABLE I.---ACUTE TOXICITY [given in LDno by intravenous injection inmice] 1 Mg./kg. a-Mercaptopropionylglycine 2,170 BMercaptopropionylglycine 3,000

Thioctic acid 197 Thioglycolicacid 315 TABLE IL-ANTIDOTAL EFFECT 'IOCORROSIVE SUBLIMATE (MERCURY) [Given as number of test mice which died]TABLE lllL-ANTIllO'lAL EFFECT 'lO OXYPHENARSINE .(ARSENIC COMPOUND)[Given in numbers at test. mice which died] ilonrs after administrationin mice given tum/kg. oxypln-narsino plus 31K) ln n/kg.fl-nterunptopropiotlylglyclne 20 mice given 30 nun/kg. oxyplmnarslnc(Control) lll mice given 30 in /kg. nxypht-nnrslttv pins can tug/kg.n-nwrca itoproplonylglyclnc (Total) Rate of (loath,

percent eal reaction so that aor iimercaptopropionylglycine is obtained.f

The reactions are illustrated by the following chemical reactions:

The following non-limitative examples are illustrative of this phase ofthe invention.

Example I a-Benzylmercaptopropionic acid (M. Pt. 76-78" C.; g.) preparedby condensation of a-mercaptopropionic acid with bcnzyl chloride isallowed to stand overnight with 80 g. of thionyl chloride. After removalof excess thionyl chloride distillation in vacuo gives 70 g. ofubenzylmercaptopropionic acid chloride of B. Pt. 138- 139" C./78 mm. Hg.1

Then, 25 g. of glycine is dissolved in m1. of 2 N sodium hydroxidesolution and 70 g. of u-benzylmerc-apto propionic ncid chloridc and 100ml. of 2 N sodium hydroxide solution are dropped thereintosimultaneously at 3 to C. The solution is then stirred at roomtemperature for 3 to 4 hours to complete the reaction, the reactionsolution is washed with other, the aqueous layer is acidified withhydrochloric acid, and the resulting crystals are collected byfiltration. These are recrystallized from a mixture of methanol andethyl acetate to give 60 g. of a-benzylmercaptopropionylglycine of M.Pt. 133-134 C.

This a-benzylmercaptopropionylglycine (60 g.) is dissolved in 400 ml. ofliquid ammonia, kept at about -50 C., and 12 g. of sodium metal isgradually added thereto. After the reaction, excess ammonia is removedtherefrom, the residue is dissolved in water, washed with ether and theresidual aqueous layer is adjusted to 'pH 1 with hydrochloric acid andconcentrated in vacuo in a stream of hydrogen sulfide. The crystallineresidue is dried and recrystallized .from ethyl acetate to give 25 g. ofamercaptopropionylgly'cine of M. Pt. 95-97 C.

Analysis calculated from C H O NS.-C, 36.80%; H, 5.56%. Found: C,37.07%, H, 5.65%.

Example 11 To 50 g. of fi-benzylmercaiptopropionic acid (obtained bycondensation of fi-mercaptopropionic acid with benzyl chloride) is added40 g. of thionyl chloride, kept overnight, and the product distilled invacuo to give 46 g. of 8-benzylmercaptopropionyl chloride of B. Pt. 150-152 C./7 mm. Hg. v I

Glycine (16 g.) is dissolved in 220 ml. of 1 N sodium hydroxidesolution, kept at approximately 5 C., and 46g. offi-benzylmercaptopropionyl chloride and 330ml. of 1 N sodium hydroxidesolution are dropped thereinto simultaneously. Then it is treated as inExample I so that 40 g. of p-benzylmercaptopropionylglycine of M. Pt.115-117 C. is obtained. fi-Benzylmercaptopropionylglycine (40 g.) isdissolved .in 260 ml. of liquid ammonia, kept at 50" C., and 8 g. ofsodium metal is gradually added thereto. After the reaction, excessammonia is removed, the residue is dissolved water, the aqueouslayeriswashed with ether, passed through a column of ion exchange resin ofstrong acid type to remove sodium, and the aqueous solution isconcentrated in vacuo to give a crystalline residue. This isrecrystallized from ethyl acetate to give 16 g. offi-mercaptopropionylglycine of M. Pt. 100.5-102 C.

Analysis calculated as C H O NS.C, 36.80%; H, 5.56%. Found: C, 37.12%;H,5.48%.

Example II! To 21g. of a-benzoylmercaptopropionic acid (M. Pt. 66.5-67.5C.; obtained by condensation of a a-mercaptopropionic acid with benzoylchloride) is added 14 g. of thionyl chloride, kept overnight, excessthionyl chloride removed therefrom in vacuo, and the residue isdissolved in 100 ml. of ether. This is washed with water, dried withsodium sulfate, and is dropped into a solution of 7.5 g. of glycine and4g. of sodium hydroxide in 100 ml. of water at 0 C., together with asolution of 4 g. to sodium hydroxide in 50 ml. of water. This is keptovernight, sodium bicarbonate is added thereto, the ethereal layer iswashed with water, and the washing is combined with the aqueous layer.This is acidified with hydrochloric acid, cooled, the resultingprecipitate is collected and dried, and recrystallized from a mixture ofethylacetate and methanol to give 8 g. ofa-benzoylmercaptopropionylglycine of M. Pt. 159.5-l60.5 C.

a-Benzoylmercaptopropionylglycine (8 g.) is addedto a solution of 9.5 g.of barium hydroxide in 50 ml. of water, heated on a water bath for 4hours, sulfuric acid is added thereto, then saturated with hydrogensulfide,

the resulting precipitate is removed by filtration, the filtrate isconcentrated in vacuo, and the residue is dried and recrystallized fromethyl acetate to give 2 g. of a-mercnptopropionylglycinc of M. Pt.94-97C.

Example IV As an Example ill, a-p-nitrobenzoylmercu-ptopropionic acidobtained by condensation of wmercaptopropionic acid with p-nitrobenzoylchloride is treated with thionyl chloride, the resulting acid chlorideis condensed with glycine, and the obtaineda-p-nitrobenzoylmercaptoprothen condensed with glycine to producect-P-tlitt'ObCi'iZYlmercaptopropionylglycine of M. Pt. 148-149 C. Thisis reduced with sodium metal in liquid ammonia as in Example I to yieldtit-mercaptopropionylglycine.

The present invention also includes the preparation of an or,S-mercaptopropionylglycineamide comprising the the steps of protectingthe mercapto radical of u- 0r fi-mercaptopropionic acid by a subtituentwhich can be readily removed, halogenating with a conventionalhalogenating agent to convert the carboxyl radical to the correspondingacid halide, condensing with glycineamide or with a glycine ester,treating with ammonia, and from the resulting S-substituted aorfl-mercaptopropionylglycineamide, removing the substituent by a suitablechemical reaction so that the desired 01- orfi-mercaptopropionylglycineamide is obtained.

The procedure is illustrated in the following chemical reactions:

oH5oHoooH oHr-oa-o 0x mN-c Hroooa' R S-R lHzN-CHr-C ONHI C Hr-C H-0 0NH-OHr-C O 0 R NH:

I SR C11 4) II-CONILCH CONH, OIL-C H-CO NH-CHz-CON H S-R -R(a-Mercaptopro ionylglyclnenmt 0) wherein R is a radical readilyconvertible to hydrogen such as, for example,

TABLE I. ACUTE TOXICITY (LD [Intravenous injection in mice] Mg./kg.a-Mercaptopropionylglycineamide 1,5 ,J-Mcrcaptopropionylglycineamide1,79O Thioctic acid 197 Thioglycolic acid 315 TABLE lL-ANTIDOIAL EFFECTT0 CORROSIVE SUBLIMATE {Given as number of test mice which died] micegiven 20 mice given 20 Hours after 4Q mice given 20 ing/kg. snblimateplus "UL/k2. sublinrate plus administration mgJktz. oi suhlinnrtc 500ing/kg. a-mercnp- .500 min/kg. B-mereap- (Control)topropionylglycinotopropionylglycinctnnitlo amide I) (l 0 it i) l .54 l0 a 2 4 (Total). r /40 3/20 5/30 Rule of tlnutlr, percent 15 17 TABLEnrl-sn'rmorar. EFFECT r0 OXYPHENARSINE (ARSENIC The'followingnon-limiiative examples are illustrative of this phase of the invention.

' Example VI a-Benzylmercaptoproprion-ic acid (obtained by thecondensation of a-mercaptopropionic acid with benzyl chloride) isreacted with thionyl chloride to give a-benzyl- 'mercaptopropionicchloride-of B. Pt. 133-139 C./7-8

mm. Hg. Glycineamide hydrochloride (3! g.) is dissolved in 150 ml. ofwater, kept at 2 to 5 C., 360 ml. of 1 N sodium hydroxide solution isadded thereto, and 55 g. of the above-obtained a-benzylmercaptopropionicchloride and 270 ml. of 2 N sodium hydroxide solution are droppedthereinto simultaneously. This is stirred at room temperature for 3 to 4hours to complete the reaction, the resulting crystals are collected,and recrystallized 0 from ethyl acetate yielding 35 g. ofa-benzylmercaptopropionylglycineamide- (M. Pt. 8890 C.). This isdissolved in ml. of liquid ammonia, kept at approximately 50 C., 7 g. ofsodium metal is added gradually thereto, and reduction reaction carriedout. After the reaction, ammonia is removed therefrom, the residue isdissolved in methanol, methanolic hydrochloric acid is added thereto tomake slightly acid, the resulting precipitalc-is removed, the motherliquor is concentrated in vacuo in a stream of hydrogen sulfide and theresulting crystals are recrystallized froma mixture of ethyl acetate andmethanol to give 12' got a-mercaptopropionylglycineamide of M. Pt.133-134 C.

Analysis calculated as C H O N S.-C, 37.02%; H,

v 6.15%; N, 17.27%. Found: C, 36.84%; H, 6.21%; N,

Example VII pleted, the ethereal layer is isolated, washed with dilutedhydrochloric acid, sodium bicarbonate solution and water, successively,then dehydrated, and the ether removed therefrom to giveB-bcnzylmercaptopropionylglycine ester as a residue. To this is addedmi. of methanolic ammonia, kept for about 7 days, and the resultingprecipitate recrystallized from methanol to give 35 g. offl-bcnzylmercaptopropionylglycineamide of M. Pt. 140.5- 14l-5 C. Debenzylation is carried out as in Example VI using sodium metal in liquidammonia, ammonia is removed therefrom and alcohol added to the residue.

.Alcoholic' hydrochloric acid is added thereto to make acid to Congored, the resulting precipitate is collected and eluted with hotanhydrous alcohol. The eluate is cooled and the isolated crystals arepooled with crystals obtained by concentration of the mother liquor.These combined crystals are recrystallized from alcohol to yield 13 g.of [3-me'rcaptopropiony-lglycincamide of M. Pt. 142l43 C.

Analysis calculated for C H O N S.-C, 37.02%; H, 6.15%; N, 17.27%.Found: C, 36.78%; H, 6.30%; N, 17.04%.

The present invention further relates to-prooedure for preparing no andfl-mercaptopropionylglycine and amide and ester derivatives thereof,useful not only for prevention and therapy of intoxicating diseasescaused by various kinds of heavy metals or intoxicating symptoms causedby administration of anti-cancer drugs or by irradiation of radioactiverays (cg. leukopenia) but also as antidotes for'snake venom such as thevenom of Trimeresurus riukiuanus and of vipers.

The procedure for preparing a:- or fi-rnercaptopropionylglycine andamide and ester derivatives thereof comprising reacting aorp-halogenopropionylglycine or amide or ester derivatives thereof withsulfur compounds (which,

tration.

96 C.) is obtained.

. of this phase of the invention.

'Exqmple VIII ti-Bromopropionylglycinc (10.5 g.) is dissolved in 30 ml.of water and neutralized by the addition of sodium bicarbonate.- To thisis added a solution of 7.5 g. of thiobenzoic acid and 4.8 g. ofpotassium carbonate in 50 ml. of water and kept overnight. On the nextday, the solution is filtered so that isolated small amounts ofinsolublematter are .removed, then the filtrate is acidified by addi- .tion ofhydrochloric acid and the resulting precipitate is collected, washedwith water and dried to give 12.8 g. of abenzoylmercaptopropionylglycine of M. Pt. 158 to 161 C.

The obtained 89 g. of a-benzoylmercaptopropionylglycine is suspended in18 ml. of water and dissolved by neutralizing with sodium bicarbonate.Concentrated ammonia water (9'ml.)- is added to this solution, keptover- .night and filtered. The separated benzoic acid amide'is washedwith a small volume of water and this washing is combined with thepreviously obtained filtrate. From this combined solution excess ammoniawater is removed as completely as possible in vacuo, then acidified withhydrochloric acid, concentrated in vacuo to /z. its volume and cooled.The isolated crystals are collected by fil- When dried andrecrystallized from ethyl acetate, 2.95 g. ofa-rnercaptopropionylglycine (M. Pt. 94-

Exantple IX @Bromopropionylglycine (10.5 g.) is dissolved in ml. ofethanol containing 2.8 g. of potassium hydroxide, 4.2 g. of thioaceticacid is added thereto, and allowed to stand at room temperature for 2days. The precipitated potassium bromide is removed, the filtrate isconcentrated in vacuo, ether is added thereto to remove insolublematters, and the ethereal solution is dried with anhydrous sodiumsulfate, evaporated to remove solvent, and kept in a refrigerator withaddition of petroleum-ether until crystals form. This is filtered andthe recovered crystals are washed with a small volume of ether-petroleumether and then dried-to give 4.2 g. of u-acetylmercaptopropiom ylglycine.meltingat 85-87 C. after purification from ethyl acetate.

Then, 4.2 g. of a-acetylmercaptopropionylglycine is dissolved in 30 ml.of 2 N sodium hydroxide solution, heated for 30 minutes, neutralizedwith hydrochloric acid, and concentrated to dryness in vacuo. Theresidue is recrystallized from ethyl acetate to yield 1.9 g. ofa-mercaptopropionylglycine.

7 Example X a-Bromopropionylglycine (10.5 g.) is dissolved in 100 ml. ofwater, neutralized by addition of 4.2 g. of sodium bicarbonate, and iskept overnight with addition of 9.0 g. of potassium xanthogenate. Thisis filtered, the filtrate is'acidified with hydrochloric acid, theresulting precipitate is collected, washed with water, dried, andrecrystailized from 30% methanol to give 10.8'g. ofa-ethylxanthogenpropionylglycine of M. Pt. 112-1 13.5" C.

To 8.4 g. of a-ethylxanthogenpropionylglycine is added ml. ofconcentrated ammonia water at a temperature below 15 C. This is kept for2 days, then the resulting xanthogenamide is removed by extracting with50 ml. of ether, nitrogen gas is passed into the residual aqueoussolution to remove excess of ammonia, acidified with hydrochloric acid,saturated with sodium chloride, and kept in a refrigerator untilcrystals appear. These are collected by filtration, dried in adesiccator (phosphorus pentoxide) in vocuo, and recrystallized fromethyl acetate to give 1.7 g. of a-rnercaptopropionylglycine.

Example XI a-Bromopropionylglycine (10.5 g.) is dissolved in 15 ml. ofwater, neutralized with 4.2 g of sodium bicarbonate, and heated ona-water-bath with 13.7 g. of sodium thiosulfate (pentahydrate) for 2hours. This is cooled, hydrochloric acid is" added thereto to decomposeexcess sodium thiosulfate, and filtered. The filtrate is made alkalinewith sodium hydroxide and allowed to stand for 2 days. The reactionsolution is then diluted with water to make ml. passed through a columnof ion exchange resin of strong acid type to remove cations, andconcentrated to dryness in vacuo. The crystalline residue is dried andrecrystallized from ethyl acetate to give 1.8 g. ofa-mercaptopropionylglycine.

Example XII I 'Thiobenzoic acid (7.6 g.) is dissolved in 50 ml. ofethanol containing}! g. of potassium hydroxide, 10.5 g.of.a-bromopropionylglycineamide is added thereto, and let stand at roomtemperature for 2 days. The reaction solution together with theprecipitate which forms. is concentrated to V3 its volume in vacuo,allowed to stand with 50 ml. ofwatcr, and the isolated crystals arecollected. This is washed with water, dried, and recrystallized frommethanol to give 8.6 g. of m-benzoylmercaptopropionyl'glycineamide of M.Pt. 149-l50 C.

This a-benzoylmercaptopropionylglycineamide (8.0 g.) is dissolved in 40ml. of 20% ammoniacal methanol, and kept overnight. Ammonia and methanolare removed by evaporation in vacuo the next day, the residue isdissolved in water, filtered, and insoluble matter washed with water.The washing is combined with the filtrate, concentrated to dryness invacuo, the rcsidue dried and recrystallized from a mixture of ethylacctatejand methanol to give 2.2 g. of a-mercaptopropionylglycineamideof M. Pt. 133- C.

Example XIII Glycine (3.8 g.) is dissolved in 50ml. of 1 N sodiumhydroxide solution and 8.5 g. of B-bromopropionylchloride and 25 ml. of2 N sodium hydroxide solution are dropped thereinto simultaneously at 3to 5 C. The solution is then stirred at room temperature for 3 to 4hours. To this resulting solution is added a solution of 7.5 g. of

- thiobenzoic acid and 4.8 g. of potassium carbonate in 50 ml. of waterand kept overnight. On the next day, the solution is filtered, then thefiltrate is acidified by addition of hydrochloric acid and the resultingprecipitate is collected, washed with water and dried to give 11.4 g. of8-benzoylmercaptopropionylglycine of M. Pt. 129 to 130.5 C.

The obtained 8.0 g. of p-benzoylmercaptopropionylglycine is dissolved in5 N sodium hydroxide solution, heated for one hour, neutralized withhydrochloric acid and concentrated to dryness in vacuo. The residue isrecrystal- 9 lized from ethyl acetate to yield 2.5 g. of B-mercapto-Thiobenzoic acid (7.6 g.) is dissolved in 50 ml. of ethanol containing3.1 g. of potassium hydroxide, 11.9

g. of a-bromopr'opionylglycine ethyl ester is added thereto, and keptovernight., The precipitated potassium bromide is removed by filtrationthe next day, the filtrate is concentrated in vacuo, and residual oil isdissolved in ether. This is washed with water, an aqueous solution ofsodium bicarbonate and water, successively, then dried with anhydroussodium sulfate, and the ether removed by evaporation. When petroleumbenzene is added thereto and allowed to stand, crystallization occursand the crystals are collected by filtration and Washed with a mixtureof ether and petroleum benzene to give 13.2 g. ofa-benzoylmercaptopropionylglycine ethyl ester which melts at 75- 77 C.when recrystallized from 60% ethanol.

This a-benzoylmercaptopropionylglycine ethyl ester (8.9 g.)is dissolvedin 100 ml. of liquid ammonia, let stand for about 60 hours, and theammonia removed therefrom. The resulting crystals are dissolved in waterto remove insoluble benzoic acid amide, and the filtrate is concentratedto dryness in vacuo. The residue is recrystallized from a mixture ofethyl acetate and methanol to give 1.8 g. ofa-mercaptopropionylglycineamide.

From the ethyl acetate-insoluble part, 3.5 g. ofbis-(amercaptopropionylglycineamide) (M. Pt. 165-167 C.: oxide type) isobtained as a side product.

Example XVI As in the Example XV, 112 g. of,B-benzoylmercaptopropionylglycine ethyl ester (M. Pt. 69-7l C.) isprepared starting from 11.9 g. of .p-bromopropionylgl'ycine ethyl ester.

This fl-benzoylmercaptopropionylglycine ethyl ester (7.4 g.) is mixedwith 8.5 g. of barium hydroxide (octahydrate), 50 ml. of water, and 30ml, of ethanol, and

. heated in a nitrogen stream on a water-bath at 70-80 C.

for 8 hours. Afte'rcooling, the solution is acidified with dilutesulfuric acid, and the precipitated barium sulfate is collected byfiltration and washed with water. The washing is combined with thefiltrate and concentrated to dryness in vacuo. The residue is dried in adesiccator (phosphorus pentoxide) in vacuo and recrystallized from ethylacetate to give 1.5 g. of p-mercaptopropionylglycine of M. Pt. 101-103C.

By air-oxidation of the crude product, 1.3 g. of bis-(B-mercaptopropionylglycine) (M. Pt. 197-199 C.) is obtained as a sideproduct.

Example X VIII A mixture of 6.5 g. of sodium sulfide (nonahydrate) and0.9 g. of fiower of sulfur is dissolved in 30 ml. of

.water by heating on a water-bath, an aqueous solution and heated on awater-bath for 2 hours. A small amount of insoluble matter is removed byfiltration the next day and the filtrate is made acid with hydrochloricacid to give 6.8 g. of bis-(ii-mercaptopropionylglycine), which melts at197l99 C. after recrystallization from water.

This bis-(fi-mercaptopropionylglycine) (6.5 g.) is suspended in 65 ml.of water, dissolved by neutralizing with I addition of 3.4 g. of sodiumbicarbonate, aluminum amalgarn prepared from 6 g. of aluminum leaves isadded thereto, heated gradually, and stirred at 80-90 C. for 1.5 hours.After cooling, the precipitate is collected by filtration and washedwith water. This washing is combined with the filtrate, concentrated todryness in vacuo, and the residue is dried and recrystallized from ethylacetate to give 4.2 g. of fl-mercaptopropionylglycine.

Example XVIII A mixture of 6:5 g. of sodium sulfide (nonahydrate) and0.9 g. of flower of sulfur is dissolved in ml. of ethanol under heating,11.9 g. of 13-bromopropiony1glycine ethyl ester is added thereto, andheated to refiux on a water-bath for 2 hours. A small amount ofinsoluble matter is removed by filtration the next day, ethanol isevaporated from the filtrate in vacuo, and allowed to stand so thatisolated oil is solidified. This is filtered, washed with water and asmall volume of ethanol, and dried to give 6.4 g. ofbis-(B-mercaptopropionylglycine ethyl ester), which melts at l20l2l C.when recrystallized from ethanol.

This bis-(B-mercaptopropionylglycine ethyl ester) (6.4 g.) is dissolvedin ml. of 20% ammoniacal methanol, kept at room temperature for 5 days,concentrated, and

.the resulting crude crystals (5.4 g.) are recrystallized from water togive 4.8 g. of bis-(fl-mercaptopropionylglyeineamide) (M. Pt. 223-225"c.).

This bis(fl-mercaptopropionylglycineamide) (4.8 g.) is suspended in 100ml. of 50% acetic acid, and stirred with 2.1 "g. of zinc dust at roomtemperature for 4 hours. The next day, hydrogen sulfide is passed intothe solution .to remove zinc, filtered, the filtrate concentrated todryness in vacuo, and the residue dried in a desiccator (phosphoruspentoxide; in vacuo) and recrystallized from anhydrous ethanol to give3.2 g. of p-mercaptopropionylglycineamide of M. Pt. 142-143.5 C.

What is claimed is:

1. A mercaptopropionic acid derivative selected from the groupconsisting of CH CHR-CONHCH COA and CH; R--CH CONHCH COA in which R isselected from the group consisting of SCOCH; and SCOC H and A isselected from the group consisting of OH and NHa-Mercaptopropionylglycine.

. B-Mcrcaptopropionylglycine.

. a-Mercaptopropionylglycineamide. p-Mercaptopropionylglycineamide.

. a-Acetylmercaptopropionylglycine. a-Benzoylmercaptopropionylglycine.

References Cited by the Examiner Greenstein, Chemistry of the AminoAcids, v01. 3, pp. 1077-1092 (1961).

Reid, Organic Chemistry of Bivalent Sulfur, vol. pages 21-29 (1958).

Wagner, Synthetic Organic Chemistry, page 566 3).

LORRAINECA. WEINBERGER, Primary Examiner. DANIEL D. noawrrz, LEONZITVER, Examiners.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,246,025 April 12, 1966 Itaru Mita et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 4, lines 36 to 46, the reaction mechanism should appear as shownbelow instead of as in the patent:

CH CH-CONHCH COOR NH CH -CHCONH-CH -CONH -R S-R CH CH-CONH-CH CONH(aMercaptopropionylglycineamide) Signed and sealed this 7th day ofFebruary 1967r (SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A MERCAPTOPROPIONIC ACID DERIVATIVE SELECTED FROM THE GROUPCONSISTING OF CH3CHR-CONHCH2COA AND CH2R-CH2CONHCH2COA IN WHICH R ISSELECTED FROM THE GROUP CONSISTING OF SCOCH3 AND SCOC6H5 AND A ISSELECTED FROM THE GROUP CONSISTING OF OH AND NH2.